Tissue-adhesive substances can be applied not only to various medical fields such as wound healing, adhesion of surgical tissue, hemostasis, etc., but also to a drug-delivery system and tissue regeneration, and therefore, the possibility of its potential utilization is highly evaluated. Representative tissue-adhesive substances include a fibrin adhesive or a cyanoacrylate-based substance, but since problems associated with concerns of infection and toxicity have occurred, it is necessary to discover safe substances exhibiting excellent tissue adhesiveness. Additionally, because most tissue-adhesive substances currently in use are sensitive to moisture, adhesion strength of substances containing adhesiveness may significantly be decreased depending on the application environment. In particular, the adhesiveness tends to be deteriorated, lost, or desorbed at the time of application to a living body, and therefore, there is a possibility that frequent reapplication of tissue-adhesive substances is required.
A temperature-sensitive hydrogel shows a sol-gel phase transition in which a liquid state, e.g., a sol form, is maintained at a low temperature but converts into a gel as the temperature rises. This is advantageous in that since a temperature-sensitive hydrogel is injected in a liquid form, the hydrogel can be evenly distributed to a lesion even if tissues therein to be applied exist in any shape, and immediately forms a gel having a three-dimensional structure due to body temperature. Accordingly, it can effectively exist in a form suitable for an application site, thereby having a potential as a tissue-adhesive substance. In addition, it is advantageous in that the hydrogel can be treated by mixing with various substances that are useful for tissue adhesion. However, it is known that the temperature-sensitive hydrogel has difficulty in a clinical application due to low tissue adhesiveness, strength, and rapid loss.
The present inventors found from previous studies that phosphazene-based polymers obtained by substituting a dichlorophosphazene linear polymer with an amino acid ester and methoxypolyethylene glycol exist in a liquid state below a certain temperature. However when the temperature exceeds a certain temperature, it was confirmed that the phosphazene-based polymers retained a property as a temperature-sensitive polymer which exhibits a sol-gel phase transition in a gel form having a three-dimensional structure (Korean Patent Nos. 10-0259367 and 10-0315630).
On the other hand, in the case of catechol, which occupies the majority of adhesion proteins extracted from mussels, it not only has resistance against moisture but also exhibits strong adhesion, excellent resilience, and no toxicity. Therefore, there has been an increase in the possibility of applying the catechol as an adhesive substance. Furthermore, research on a hydrogel having adhesiveness by using the above tendencies has also been reported.
Accordingly, the present inventors made extensive efforts to discover temperature-sensitive and tissue-adhesive polymers with improved adhesiveness of tissues by modifying phosphazene-based polymers having biodegradability and temperature-sensitivity. As a result, it was confirmed that polymers in which a moiety having a functional group in addition to an amino acid ester and methoxypolyethylene glycol is introduced followed by linking a catechol group at a predetermined ratio exhibited a sol-gel transition at a temperature near the body temperature. Therefore, it was also confirmed that it causes the polymers to be converted into a hydrogel form while enhancing the adhesiveness of tissues so that a polymer hydrogel with improved adhesion of a wound can be provided when applied to a human body, thereby completing the present invention.